WO2020095880A1 - Tight junction modulator, absorption promoter of compound comprising modulator, and pharmaceutical composition, quasi-drug composition, cosmetic composition, and food composition comprising modulator as active ingredient - Google Patents

Abstract

The present invention addresses the problem of providing a tight junction modulator that comprises a compound which is already on the market as a medicine or is already used as a quasi-drug or the like and which modulates tight junctions.　This problem can be solved by a tight junction modulator which comprises at least one selected from the compounds represented by formulas (1) to (4) and at least one selected from pharmaceutically acceptable salts of the compounds represented by formulas (1) to (4).　[Chem. 1]

Description

Tight junction mitigating agent, absorption enhancer of compound containing the mitigating agent, and pharmaceutical composition, quasi drug composition, cosmetic composition and food composition containing the mitigating agent as an active ingredient

The present disclosure relates to a tight junction alleviating agent, an absorption enhancer of a compound containing the alleviating agent, and a pharmaceutical composition, a quasi drug composition, a cosmetic composition and a food composition containing the alleviating agent as an active ingredient. ..

In order to maintain homeostasis in the body, it is important to contain water, sugar, ions, etc. in the body. Epithelial cells are cells that play a role of separating the outside world from the inside, and a cell adhesion device that connects the cells has been developed. Of the several cell adhesion devices that exist, the outermost one is a tight junction. Tight junctions are formed by the strong interaction of the membrane protein claudin between epithelial cells and prevent free permeation of water and ions. The function of such a tight junction is particularly important in the blood-brain barrier, which keeps the skin moist and prevents foreign substances from entering the brain. Therefore, substances that control the formation of tight junctions have attracted attention as targets for the development of cosmetics and medical products.

For example, the following compounds are known as compounds that reduce tight junctions (see Patent Document 1).

 

 

International Publication No. 2016/190310

The compounds described in Patent Document 1 above are useful compounds that relieve tight junctions, but they are not compounds approved as pharmaceuticals. Therefore, it is expected that it will take time to bring it to market. On the other hand, if a compound that has already been put on the market as a drug or is already used in a quasi drug or the like is found to be used for alleviating tight junction, it may be possible to provide it to the market early.

The present disclosure has been made to solve the above problems, and has been already marketed as a pharmaceutical product, or a tight junction mitigating agent containing a compound already used in a quasi drug, etc., and a compound containing the mitigating agent. It is an object of the present invention to provide a pharmaceutical composition, a quasi drug composition, a cosmetic composition, and a food composition, which contain the absorption promoter of the above, and the emollient as an active ingredient.

The present disclosure shows a tight junction easing agent, an absorption enhancer of a compound containing the easing agent, and a pharmaceutical composition, a quasi drug composition, a cosmetic composition, and a composition containing the easing agent as an active ingredient. Food composition.

［２］上記［１］に記載のタイトジャンクションの緩和剤を有効成分として含む化合物の吸収促進剤。
［３］上記［１］に記載のタイトジャンクションの緩和剤を有効成分として含む医薬組成物。
［４］上記［１］に記載のタイトジャンクションの緩和剤を有効成分として含む医薬部外品組成物。
［５］上記［１］に記載のタイトジャンクションの緩和剤を有効成分として含む化粧品組成物。
［６］上記［１］に記載のタイトジャンクションの緩和剤を有効成分として含む食品組成物。 [1] At least one selected from the compounds represented by the following formulas (1) to (4), or
At least one selected from pharmaceutically acceptable salts of compounds represented by the following formulas (1) to (4):
Tight junction mitigating agent, including.

[2] An absorption enhancer of a compound containing, as an active ingredient, the tight junction mitigating agent according to the above [1].
[3] A pharmaceutical composition comprising the tight junction easing agent according to [1] above as an active ingredient.
[4] A quasi drug composition containing, as an active ingredient, the tight junction mitigating agent according to [1].
[5] A cosmetic composition comprising the tight junction easing agent according to [1] above as an active ingredient.
[6] A food composition containing the tight junction mitigating agent according to [1] above as an active ingredient.

The tight junction mitigating agent disclosed in the present specification can alleviate tight junction by using a compound that has already been used as a drug or the like. Therefore, the time to be provided to the market can be shortened as compared with the novel compound.

FIG. 1 is a graph showing the results of a cell permeability test. FIG. 2 is a graph showing the results of the cell permeability test.

Hereinafter, a tight junction mitigating agent (hereinafter, may be simply referred to as “relaxing agent”) and an absorption enhancer of a compound containing the mitigating agent as an active ingredient (hereinafter, simply referred to as “absorption enhancing agent”) And a pharmaceutical composition containing the emollient as an active ingredient (hereinafter sometimes simply referred to as “pharmaceutical composition”), and a quasi drug composition containing the palliative as an active ingredient. (Hereinafter, may be simply referred to as “quasi drug composition”), cosmetic composition containing the emollient as an active ingredient (hereinafter, may be simply referred to as “cosmetic composition”). And each embodiment of a food composition containing the emollient as an active ingredient (hereinafter, may be simply referred to as “food composition”).

The relaxation agent according to the embodiment,
At least one selected from the compounds represented by the following formulas (1) to (4), or
At least one selected from pharmaceutically acceptable salts of compounds represented by the following formulas (1) to (4):
It is characterized by including.

The compound represented by the above formula (1) ({1-[(4-chlorophenyl) carbonyl] -5-methoxy-2-methyl-1H-indol-3-yl} acetic acid) is generally indomethacin. It is called (indometacin) and is known to have an anti-inflammatory action and an analgesic action. Known examples of the drug containing the compound represented by the above formula (1) as an active ingredient include Intevan (Teikoku Pharmaceutical Co., Ltd.) and Akonip Pap (Taika Pharmaceutical Co., Ltd.). In addition, as a drug containing the sodium salt of the compound represented by the above formula (1) as an active ingredient, indacine intravenous injection (Nobel Pharma) and the like are known.

The compound represented by the formula (2) (2- (2- (2,6-dichlorophenylenamino) phenyl) acetic acid) is generally called diclofenac, and has arthritis, gout, and kidney. It is known to have an analgesic action against stones, urinary tract stones, migraine, etc., and an anti-inflammatory action. Nabor (Kumitsu Pharmaceutical Co., Ltd.), Voltaren (Novartis Pharma), etc. are known as pharmaceuticals containing the sodium salt of the compound represented by the above formula (2) as an active ingredient.

The compound ((2S, 3S, 4S, 5R, 6S) -6- (5,6-dihydroxy-4-oxo-2-phenyl-chrome-7-yl) oxy-3, represented by the above formula (3) 4,5-trihydroxy-tetrahydryran-2-carboxylic acid is generally called baicalin. Baicalin is known as an ingredient contained in Ougon, which is a herbal medicine in which the roots of the Perillaceae Scutellaria baicalensis excluding the pericardium are dried, and is used in many prescriptions because it has a heating effect and an anti-inflammatory effect in Chinese medicine. There is. It is also used in skin care products and hair restorers because it has a moisturizing and whitening effect. Known Chinese herbs containing the compound represented by the above formula (3) include Uchida powder (Ouchida Japanese medicine). Further, as cosmetics containing the compound represented by the above formula (3), be-10 Premium Biocell Eye Sheet (manufactured by Afra), Genomer BB Perfect Cream (manufactured by Dr. Sea Lab) and the like are known.

The compound represented by the above formula (4) (5,6,7-Trihydroxy-2-phenyl-chrome-4-one) is generally called baicalein. Baicalein, like baicalin, is known as a component contained in Ougon, which is a herbal medicine in which the root excluding the pericarp of Lamiaceae is removed, and it is known to have many prescription and anti-inflammatory effects in Chinese herbs. Is compounded in. In addition, as a cosmetic raw material containing baicalin or baicalein as a functional ingredient, Ougon extract powder (manufactured by Ichimaru Falcos Co., Ltd.) and the like are commercially available. As cosmetics containing Ougon root extract, GE Power Serum (manufactured by DHC), Satishé Rush condition mascara base (manufactured by CP Cosmetics) is known.

In the present specification, the “pharmaceutically acceptable salt” means a salt having the effectiveness of the above compound and not biologically harmful. For example, but not limited to, a salt formed by combining the above compound with an acid or a base. The pharmaceutically acceptable salts may exist as various solvates with, for example, water, methanol, ethanol, dimethylformamide and the like.

The emollients disclosed in the present specification can be used for absorption promoters of compounds, pharmaceutical compositions, quasi drug compositions, cosmetic compositions, food compositions and the like. The dosage forms include, for example, thin film, powder, pills, tablets, injections, suppositories, emulsions, capsules, granules, liquids (tinctures, flow extracts, spirits, suspensions, limonade agents). Etc.) and the like. Further, within a range that does not impair the effects disclosed in the present specification, various components used in ordinary medicines, quasi drugs, cosmetics, foods, etc., such as oily ingredients, emulsifiers, humectants, thickeners, and medicinal ingredients. , Antibiotics, antibacterial agents, hormonal agents, supplements, preservatives, powders, pH adjusters, ultraviolet absorbers, antioxidants and the like can be appropriately added.

In this specification, when the terms "medicine", "quasi-drug", and "cosmetics" are used, it is in accordance with the provisions of the "Law Concerning Quality, Effectiveness, and Safety of Pharmaceuticals, Medical Devices, etc." in Japan. .. More specifically, when described as “medicine”, it means “those intended to be used for diagnosis, treatment or prevention of illness (disease)”. In addition, in this specification, a "medicine" means a pharmaceutical for humans and animals. In addition, when described as “quasi drug”, “it is not used for treatment positively, but is used for the purpose of preventing discomfort such as nausea, rash, soreness, etc. It is used for cosmetic purposes such as body odor, prevention of hair loss, hair growth, hair removal, etc. It has a mild effect on the human body. " In addition, when described as "cosmetics", it is intended to be used for "cleansing, beautifying, increasing the attractiveness, changing the appearance of the human body, or keeping the skin or hair healthy." It has a mild effect on the human body. " However, the above-mentioned provisions regarding "medicines", "quasi-drugs", and "cosmetics" are based on the "Law Concerning Quality, Effectiveness, and Safety of Pharmaceuticals, Medical Devices, etc." in Japan. In countries other than Japan, the provisions of laws that correspond to or are similar to the "Law Concerning Quality, Effectiveness, and Safety of Pharmaceuticals, Medical Devices, etc." of that country shall apply. Further, the "food" is not particularly limited as long as it can be ingested by humans or animals, and for example, fresh food, animal food, vegetable food, fungal food, processed food, health food, and beverage. And seasonings. When the term "compound" is used in the present specification, (1) the "medicine", "quasi drug", "cosmetic" and "food" itself, or the "medicine", "quasi drug" , “Cosmetics” and “Foods”, and (2) Compounds that are not classified into the above “Pharmaceuticals”, “Quasi-drugs”, “Cosmetics” and “Foods”, but do not adversely affect the human body Means ,.

When the emollient disclosed in this specification is used as an absorption enhancer of a compound, it may be used in combination with the compound to be absorbed.

The "pharmaceutical composition" disclosed herein is, for example, a "pharmaceutical product" such as a transdermal drug, a transmucosal drug such as nasal / enteral drug, an injection drug, an eye drop drug, an inhalation drug, and the like, The "relaxation agent" disclosed in the present specification may be added as an active ingredient.

The "quasi-drug composition" disclosed in the present specification includes, for example, a mouthwash, a medicated dentifrice, a medicated soap, a medicated cosmetic, an antiperspirant spray, an axillary deodorant, a bath agent, and a medicated cream. The "relaxation agent" disclosed in the present specification may be added as an active ingredient to "quasi-drugs" such as baby powder, hair growth / hair nourishing agents, and hair dyes.

The "cosmetic composition" disclosed herein includes, for example, basic cosmetics such as milky lotion, cream, lotion, essence, pack, and face wash; makeup cosmetics such as lipstick, foundation, liquid foundation, and makeup pressed powder. The "relaxing agent" disclosed in the present specification may be added as an active ingredient to "cosmetics" such as cleansers, body shampoos, soaps and other cleaning cosmetics.

The "food composition" disclosed in the present specification is, for example, "food" such as fresh food, animal food, plant food, fungal food, processed food, health food, beverage, seasoning, etc. exemplified above. In addition, the "relaxation agent" disclosed in the present specification may be added as an active ingredient.

Each embodiment will be specifically described below with reference to examples, but the examples are provided merely as a reference for specific aspects thereof. These examples do not limit or limit the scope of the invention.

[Compound cell assay]
(1) Compound As the compound, the compounds described in the above formulas (1) to (4) were used. The compounds described in formulas (1), (3) and (4) were purchased from Tokyo Chemical Industry Co., Ltd. Further, the compound represented by the formula (2) was purchased from Merck-Millipore.

(2) Cell Permeability Test Standard medium (Minimum Essential Medium Eagle made by SIGMA, 10% v / v Bio Bovine Serum, Petal Bovine Serum, 1% v / v Gibco penicillin / Streptomycin, 1% EbAvAvGvAv). Cultured Caco-2 cells (purchased from RIKEN BRC CELL BANK, deposit number: RCB No. 0988) were seeded in an upper tank of a millicell-24 cell culture plate (manufactured by Merck-Millipore), and continuously cultured for 2 weeks. An epithelial cell sheet was formed. During the culture, the medium was replaced every two days. After completion of the culturing for 2 weeks, formation of an epithelial cell sheet was confirmed by a transepithelial electrical resistance test.

A medium for permeability test was prepared by mixing the following (1) to (3). Incidentally, 0.3% v / v DMSO (manufactured by SIGMA) which does not contain the compound (2) below was used as a control.
(1) 400 μl of standard medium.
(2) A 300 μM compound in DMSO (the compounds of the above formulas (1) to (4) alone or in combination).
(3) 2.5 μg / ml FITC-insulin (manufactured by SIGMA) as a tracer.

Then, the prepared medium for permeability test and control were added to the epithelial cell sheet formed in the upper tank of the millicell-24 cell culture plate, respectively. Further, 800 μl of standard medium was added to the lower tank of the millicell-24 cell culture plate so that the lower surface of the epithelial cell sheet was in contact with the standard medium. Then, the plate was placed in a 37 ° C., 5% CO ₂ environment and incubated. After 24 hours, 100 μl of the medium was sampled from each of the lower tanks corresponding to the medium for the permeability test and the control, and added to a 96-well plate for fluorescence assay (Perkin Elmer), and a plate reader (Perkin Elmer). The fluorescence intensity was measured using EnSpire (manufactured by Enspire). Since this fluorescence originates from FITC-insulin which has permeated the epithelial cell sheet and moved to the lower tank, the fluorescence intensity increases as the tight junction of the epithelial cell sheet becomes looser due to the compound added to the upper tank. That is, it can be said that the compound having a high fluorescence intensity has a high effect of relaxing the tight junction.

1 and 2 show the results of the cell permeability test. As is clear from FIGS. 1 and 2, even if any of the compounds of formulas (1) to (4) was used, it was confirmed that the tight junction was alleviated since the fluorescence intensity was increased. Further, as is clear from FIG. 2, it was confirmed that even if the compounds of the formulas (1) to (4) were combined, the tight junction was alleviated.

The compounds represented by the formulas (1) to (4) disclosed in the present specification can alleviate tight junctions. Therefore, since it can be used as a compound absorption promoter, a pharmaceutical composition, a quasi drug composition, a cosmetic composition, and a food composition, it is useful for the medical industry, the cosmetic industry, and the food industry.

Claims (6)

At least one selected from the compounds represented by the following formulas (1) to (4), or
At least one selected from pharmaceutically acceptable salts of compounds represented by the following formulas (1) to (4):
Tight junction mitigating agent, including.

An absorption promoter for a compound containing the tight junction mitigating agent according to claim 1 as an active ingredient. A pharmaceutical composition comprising the tight junction mitigating agent according to claim 1 as an active ingredient. A quasi drug composition containing the tight junction easing agent according to claim 1 as an active ingredient. A cosmetic composition comprising the tight junction mitigating agent according to claim 1 as an active ingredient. A food composition containing the tight junction mitigating agent according to claim 1 as an active ingredient.

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